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Effect of interleukin-1 gene functional polymorphism on dorsolateral prefrontal cortex activity in schizophrenic patients.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:1090 –1093 (2007)
Brief Research Communication
Effect of Interleukin-1b Gene Functional
Polymorphism on Dorsolateral Prefrontal Cortex
Activity in Schizophrenic Patients
Sergi Papiol,1* Vicente Molina,2 Araceli Rosa,1,3 Javier Sanz,4 Tomás Palomo,4 and Lourdes Fañanás1
1
Departament de Biologia Animal, Unitat d’Antropologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
Department of Psychiatry, Hospital Clı´nico de Salamanca, Salamanca, Spain
3
Unitat de Biologia Evolutiva. Facultat de Cie`ncies de la Salut i de la Vida. Universitat Pompeu Fabra. Barcelona, Spain
4
Department of Psychiatry, Hospital Doce de Octubre, Edificio de Medicina Comunitaria, Madrid, Spain
2
Hypoactivity of the dorsolateral prefrontal
cortex (DLPFC) during cognitive tasks is among
the most consistent findings in schizophrenia. The
biological factors contributing to this hypofrontality are only partially known. Previous reports
have shown the influence of genes mapped to IL-1
cluster (i) in the risk to develop schizophrenia
and (ii) on brain morphological abnormalities in
these patients. Moreover, Interleukin-1b (IL-1b),
encoded by IL-1B gene (IL-1 cluster, chromosome
2q13) has a key role in dopaminergic differentiation and dendrite growth in developing cortical
neurons. The authors explored the role of a
genetic functional polymorphism at IL-1B gene
in relation to DLPFC activity. DLPFC (left and
right) metabolic activity was measured in a
sample of 19 DSM-IV diagnosed schizophrenic
patients of Spanish origin using a procedure
based on MRI/PET image fusion. During PET
studies, subjects performed a contingent Continuous Performance Test aiming to activate DLPFC.
Functional promoter polymorphism 511 C/T
(rs16944) of IL-1B gene was genotyped in these
patients. Those patients who were allele 2 (511 T)
carriers showed a lower metabolic activity in the
left DLPFC with respect to patients homozygous
for allele 1 (511 C) (U ¼ 16, z ¼ 2.32, P ¼ 0.02). Our
results suggest that hypofrontality reported in
some schizophrenic patients might be explained,
at least in part, by this functional polymorphism
at IL-1B gene. Genetic variants with influence on
brain functionality may account for the neurocognitive heterogeneity observed in schizophrenic patients.
ß 2007 Wiley-Liss, Inc.
Grant sponsor: Fundació ‘‘La Caixa’’; Grant numbers: 99-11100, 99-042-00; Grant sponsor: Instituto de Salud Carlos III-FIS;
Grant number: 02/3095; Grant sponsor: Spanish Ministry of
Health, Instituto de Salud Carlos III, Red de Enfermedades
Mentales (REM-TAP Network); Grant number: RETIC RD06/
0011; Grant sponsor: Generalitat de Catalunya, DURSI; Grant
number: 2005SGR00608.
*Correspondence to: Sergi Papiol, B.Sc., Departament de
Biologia Animal, Unitat d’Antropologia, Facultat de Biologia,
Universitat de Barcelona, Av. Diagonal 645, 08028 Barcelona,
Spain. E-mail: sergi.papiol@ub.edu
Received 17 August 2006; Accepted 6 March 2007
DOI 10.1002/ajmg.b.30542
ß 2007 Wiley-Liss, Inc.
KEY WORDS:
Interleukin-1;
schizophrenia;
dorsolateral prefrontal cortex;
hypofrontality; PET
Please cite this article as follows: Papiol S, Molina V,
Rosa A, Sanz J, Palomo T, Fañanás L. 2007. Effect of
Interleukin-1b Gene Functional Polymorphism on
Dorsolateral Prefrontal Cortex Activity in Schizophrenic Patients. Am J Med Genet Part B 144B:1090–
1093.
INTRODUCTION
Hypoactivity of the dorsolateral prefrontal cortex (DLPFC)
during cognitive tasks is among the most consistent findings in
schizophrenic patients. Experiments based on executive or
working memory challenges (Wisconsin Card-Sorting Test,
verbal fluency, Tower of London or n-back task) typically
demonstrate hypofrontality, a reduced activity of DLPFC in
schizophrenic patients with respect to healthy subjects
[Weinberger et al., 1988; Barch et al., 2001; Glahn et al.,
2005; Snitz et al., 2005].
The neural, molecular, and genetic underpinnings of this
dysfunction and other functional/morphological brain features
are nowadays an active topic of research in schizophrenia.
Several studies have shown the influence of BDNF, DISC1, or
COMT genes, among others, on brain morphology in schizophrenia [Agartz et al., 2006; Ho et al., 2006; Ohnishi et al.,
2006]. On the other hand, few studies have analyzed the effects
of genetic variability of candidate genes on brain activity in
schizophrenia. Among them, COMT gene is a paradigmatic
example of how a single polymorphism can modulate DLPFC
activity and cognitive performance [Egan et al., 2001; Rosa
et al., 2004b].
Recent studies have revealed that genetic variants at IL-1B
and IL-1RN genes (IL-1 cluster, chromosome 2q13) might
confer risk to schizophrenia and bipolar disorder [Katila et al.,
1999; Papiol et al., 2004; Rosa et al., 2004a]. The same genetic
variants have been reported to contribute to structural brain
abnormalities such as ventricular enlargement (IL-1RN)
[Papiol et al., 2005] and frontal gray matter (GM) deficits (IL1B) [Meisenzahl et al., 2001] in schizophrenic patients.
Interleukin-1b (IL-1b), encoded by IL-1B gene, is a cytokine
involved in neurodevelopmental processes [Nawa et al., 2000]
as well as in acute and chronic neurodegeneration [Allan et al.,
2005]. Studies in vitro have shown that IL-1b has an important
role in the induction of the dopaminergic phenotype in mesencephalic neuronal precursors [Potter et al., 1999; RodriguezPallares et al., 2005] and in the regulation of dendrite growth in
developing cortical neurons [Gilmore et al., 2004].
Owing to the role of this cytokine during neurodevelopment,
and taking into account the results commented above regard-
Interleukin-1b Gene and Cortical Activity in Schizophrenia
ing case–control and morphometric association studies, it
could be suggested that subtle quantitative changes in IL-1b
expression may have consequences in functionality of the adult
brain. A possible factor modulating these kind of changes is a
functional polymorphism in the promoter region (511 C/T) of
IL-1B gene which regulates IL-1b expression, where allele 2
(511 T) promotes a higher expression of the gene with respect
to allele 1 (511 C) [Chen et al., 2006].
Our aim has been to investigate the hypothetical relationship between this functional polymorphism at IL-1B gene and
DLPFC activity in schizophrenic patients during an attentional task which challenges frontal function.
Sample included 19 schizophrenic patients of Spanish origin
(12 males); 9 out of them were first episodes (FE) (mean age
28.0 6.2 years; illness duration 3.6 2.8 years) and 10 were
chronic patients (mean age 39.5 11.2 years; duration
10.1 9.0 years). FE patients were medication naı̈ve and all
chronic patients had been treated with haloperidol for a period
longer than 1 month prior to PET acquisition, as a part of a
different protocol [see Molina et al., 2003]. Ethical approval
was obtained from Spanish local research ethic committees.
Given the potential effect of illness duration, age, and
medication on gene expression, we compared genotype and
brain activity between FE and chronic patients. Patients
provided a complete written informed consent before inclusion
in the study. All procedures were carried out according to the
declaration of Helsinki.
Image analysis: in order to determine the metabolic activity
in the DLPF cortex we used a procedure based on MRI/PET
image fusion. This methodology uses the anatomical information of the MRI to allow detailed measurement of regional
metabolic activity in the PET image [Molina et al., 2003].
MRI Protocol: magnetic resonance imaging studies were
acquired on a Philips Gyroscan 1.5T scanner using a T1weighted 3D gradient echo sequence with the following
parameters: matrix size 256 256, pixel size 0.9 0.9 mm
(FOV & 256 mm), flip angle 308, echo time 4.6 msec, slice
thickness 1.5 mm.
PET protocol: PET studies were obtained in a SIEMENS
Exact 47 tomograph, 20 minutes after injecting 370 MBq of
18FDG, while subjects performed a contingent visual Continuous Performance Test. Matrix size was 256 256 61, and
slices were 2.6 mm thick. Subjects were instructed to push a
button if T immediately followed the letter L, as presented on a
computer screen. The interstimulus interval was 1 sec. After
the placement of an intravenous line for FDG administration,
the subject began the task, which was divided into four blocks
of 5 min each, with a 1-min rest between each two blocks. FDG
was administered 1 min after initiating the task. Patients were
not performing the test anymore after being placed in the PET
camera.
Tracer activity values were proportionally normalized to the
global activity of each PET [Frackowiak et al., 1997] thus
representing relative activity. Total metabolic activity for each
region of interest (ROI) was divided by the ROI volume, thus
providing a measurement independent of the amount of tissue
sampled.
Segmentation: To obtain metabolic measurements, we used
a method for semi-automated segmentation of the brain based
on the Talairach reference system, similar to that described
in Andreasen et al. [1996]. Basically, we used a two-step
procedure [Desco et al., 2001]. The first step involved editing
the MRI to remove skull and extracranial tissue, registration of
PET and MRI, and an initial segmentation of cerebral tissues
into GM, white matter (WM), and cerebrospinal fluid (CSF). In
a second stage, we applied the Talairach reference system
[Talairach and Tournoux, 1988] to define ROIs and to obtain
final metabolic activity data (See Fig. 1). A Talairach grid was
built for each individual case.
1091
Fig. 1. Sagital view illustrating a Talairach grid built upon an edited
MRI and fused with the GM segmentation of the PET scan. The Talairach
grid cells describing the dorsolateral prefrontal region (DLPF) are highlighted. This ROI is defined as the cortex encompassed in Brodmann’s areas
8, 9, 10, and 46, according to the Talairach Atlas.
The edited MRI (without extracranial tissue) was coregistered with the PET study using the AIR algorithm [Woods
et al., 1993]. Fusion results were visually checked in all cases
and the observed co-registration was always optimal. An
initial segmentation of cerebral tissue was performed using
an automated method, currently included as a standard
processing tool in the statistical parametric mapping (SPM)
program [Ashburner and Friston, 1997]. This method classifies
all MRI pixels into four tissue types: GM, WM, CSF, and ‘‘other
tissues:’’ This segmentation was checked for inconsistencies
and manually corrected whenever necessary by an experienced
radiologist blinded to the diagnosis.
In the second stage, the ROI’s were obtained by superimposing the 3D tissue masks corresponding to WM, GM, and
CSF onto each subject’s Talairach reference grid (Fig. 1), where
the regions of interest were defined as sets of cells. On the PET/
MRI fused images, activity was measured by totaling the data
from the grid cells associated with each ROI [Desco et al., 2001].
The DLPF cortex was defined as the cortex encompassing
Brodmann’s areas 8, 9, 10, and 46 (Fig. 1).
511 C/T polymorphism (rs16944) located on the promoter
region of IL-1B gene was genotyped as described by Katila et al.
[1999]. Briefly, allele 1 (511 C) of IL-1B gene completes an
AvaI restriction site, while allele 2 (511 T) gives an intact
product.
According to previous reports highlighting allele 2 as an
allele of risk both for schizophrenia or its associated brain
abnormalities [Meisenzahl et al., 2001; Rosa et al., 2004a],
two subgroups of patients were generated: allele 2 carriers
(allele 1/allele 2 and allele 2/allele 2) (n ¼ 11) and no-carriers
(allele 1/allele 1) (n ¼ 8). There were no differences in sex
distribution, treatment, or time from onset between both
subgroups.
FE and chronic patients did not significantly differ in terms
of metabolic activity (left side FE 97.53 6.97, chronics
94.43 3.38, U ¼ 31, z ¼ 1.14, P ¼ 0.25; right side FE
102.66 7.85, chronics 100.19 3.39; U ¼ 32, z ¼ 1.06,
P ¼ 0.31) neither on distribution of genotypes (FE five
noncarriers, four carriers; chronics four noncarriers, seven
carriers, w2 ¼ 1.81, P ¼ 0.37).
We found a significantly lower metabolic activity in the left
DLPFC in those patients with at least one allele 2 (mean
93.55 5.51) with respect to patients homozygous for allele 1
(mean 99.13 3.55) (U ¼ 16, z ¼ 2.32, P ¼ 0.02) (see Fig. 2). In
the right DLPFC, differences were not significant (allele 2
carriers: mean 100.32 6.72; allele 1: mean 102.79 4.55;
1092
Papiol et al.
particular biological traits, we are increasing our power to
detect the effect of genetic variability on their expression
within schizophrenic patients.
Likewise, more research on IL-1 family of cytokines is
warranted in order to (i) unequivocally establish their role both
in neurodevelopment and in the adult brain and (ii) identify
genetic variants with a repercussion on both gene expression
and brain functionality.
In conclusion, the present finding enhances the interest of
neuroimaging-based techniques in ongoing and future genetic
studies of schizophrenia in order to understand genetic and
cognitive heterogeneity within this diagnostic group.
ACKNOWLEDGMENTS
Fig. 2. Values of metabolic activity during an attentional task for the left
DLPFC according to IL-1B genotype. Patients who were allele 2 carriers of
511 C/T polymorphism of IL-1B gene show a significant decrease (P ¼ 0.02)
in metabolic activity with respect to patients allele 1 homozygous.
U ¼ 31, z ¼ 1.07, P ¼ 0.31). Although we did not include
healthy controls in this genetic study, those metabolic
ratios in patients are very similar to those found to be
significantly lower than in healthy controls in a sample of FE
of schizophrenia partially overlapping with the present one
and using the same methodology [Molina et al., 2005].
Our results, although preliminary, suggest that 511 C/T
functional polymorphism at IL-1B gene might contribute
to explain hypofrontality reported in some schizophrenic
patients.
The present finding can be interpreted from a dopaminergic
hypothesis perspective. The view that dopaminergic system
plays a role in schizophrenia is long-standing [Carlsson,
1988]. Genetic studies focused on COMT, a key regulator of
dopaminergic neurotransmission, have highlighted the outstanding influence of dopaminergic system on DLPFC activity,
therefore, reinforcing this notion [Egan et al., 2001]. This
dopaminergic background enhances the interest of in vitro
studies showing that IL-1b is a key developmental factor
inducing a marked increase in generation of dopaminergic-like
neurons from neuronal precursors, maybe through induction
of specific receptors responsive to additional factors [Ling et al.,
1998; Potter et al., 1999; Rodriguez-Pallares et al., 2005]. It
could be hypothesized that changes in IL-1b expression, maybe
mediated by functional polymorphisms like 511 C/T, may
lead to subtle differences in neurons relevant to dopaminergic
system neurotransmission. The final repercussion of this fine
abnormality would manifest as a differential pattern of DLPFC
activity due to the fact that dopamine has an extreme
functional importance in the attentional tasks in the frontal
lobe [Fuster, 1999].
Further studies in larger samples would be necessary in
order to rule out the possibility of a spurious association in our
results because the limited sample size is certainly a remarkable limitation of the present study. However, it should be
noted that the statistical error generated by a low-sample
size could be minimized by the fact that according to our
hypothesis, molecular underpinnings of brain functionality (in
our case DLPFC activity) are influenced by a lower number of
genes than the complex phenotype of a mental disorder defined
by categorical diagnoses. Therefore, by analyzing these
The authors would like to thank the participating patients
and their families, whose generous contributions have made
this study possible. This study was supported by grants from
Fundació ‘‘La Caixa’’ (99-111-00), (99-042-00), FIS (02/3095)
and by the Spanish Ministry of Health, Instituto de Salud
Carlos III-RETIC RD06/0011, Red de Enfermedades Mentales
(REM-TAP Network). Sergi Papiol was supported by a grant of
the Ministry of Education and Culture of Spain.
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